010401 Allergy and Allergic Diseases

The New England Journal of Medicine 

Review Articles 

Advances in Immunology 

I AN R. MACKAY, M.D., AND FRED S. ROSEN, M.D., 

Editors 

ALLERGY AND ALLERGIC DISEASES 

First of Two Parts 

A.B. KAY, M.D., PH.D. 

ALLERGIC rhinitis, asthma, and atopic eczema 

are among the commonest causes of chronic 

ill health. These diseases are increasing in prevalence, 

and they add considerably to the burden of 

health care costs. In Sweden, for example, the number 

of children with allergic rhinitis, asthma, or eczema 

roughly doubled over a 12-year period, 1 and 

in the United States the annual cost of treating asthma 

is about $6 billion. 2 

The term “allergy” was introduced in 1906 by 

von Pirquet, who recognized that in both protective 

immunity and hypersensitivity reactions, antigens had 

induced changes in reactivity. 3 With the passage of 

time the word has become corrupted and is now frequently 

used synonymously with IgE-mediated allergic 

disease. It was von Pirquet’s intent that the term 

should apply to the “uncommitted” biologic response, 

which may lead either to immunity (a beneficial effect) 

or allergic disease (a harmful effect). 

The term “atopy” (from the Greek atopos, meaning 

out of place) is often used to describe IgE-mediated 

diseases. Persons with atopy have a hereditary predisposition 

to produce IgE antibodies against common 

environmental allergens and have one or more atopic 

diseases (i.e., allergic rhinitis, asthma, and atopic eczema). 

Some allergic diseases, such as contact dermatitis 

and hypersensitivity pneumonitis, develop 

through IgE-independent mechanisms and in this 

sense can be considered nonatopic allergic conditions. 

This article reviews the basis of atopic allergy, the 

diseases with which it is associated, and approaches 

to treatment. 

ATOPY AND TYPE 2 HELPER T CELLS 

All of us inhale aeroallergens derived from pollen, 

house-dust mites, and cat dander. In general, adults 

From the Imperial College School of Medicine, National Heart and 

Lung Institute, London. 

and children without atopy mount a low-grade immunologic 

response; they produce allergen-specific 

IgG1 and IgG4 antibodies, 4 and in vitro their T cells 

respond to the allergen with a moderate degree of proliferation 

and the production of interferon-g by type 1 

helper T (Th1) cells. 5-7 Persons with atopy, by contrast, 

have an exaggerated response characterized by 

the production of allergen-specific IgE antibodies; 

they have elevated serum levels of IgE antibodies and 

positive reactions to extracts of common aeroallergens 

on skin-prick tests. T cells from their blood respond 

to allergens in vitro by inducing cytokines produced 

by type 2 helper T (Th2) cells (i.e., interleukin-4, 5, 

and 13), 5,7 rather than cytokines produced by Th1 

cells (interferon-g and interleukin-2). There are many 

exceptions to this rule, but the immunopathological 

hallmark of allergic disease is the infiltration of affected 

tissue by Th2 cells. 8-10 

In utero, T cells of the fetus are primed by common 

environmental allergens that cross the placenta. 

As a result, the immune response of virtually all newborn 

infants is dominated by Th2 cells. 11 It has been 

proposed that during subsequent development the 

normal (i.e., nonatopic) infant’s immune system shifts 

in favor of a Th1-mediated response to inhaled allergens 

(a process termed “immune deviation”), 12 whereas 

in the potentially atopic infant there is a further 

increase in Th2 cells that were primed in utero. Microbes 

are probably the chief stimuli of protective 

Th1-mediated immunity. Macrophages that engulf 

microbes secrete interleukin-12, which induces Th1 

cells and natural killer cells to produce interferon-g, 

thereby shifting the immune system into an “allergyprotective” 

Th1-mediated response. Other factors may 

also influence whether Th1 or Th2 cells dominate 

the response, including the amount of allergen, the 

duration of exposure to the allergen, and the avidity 

of allergen-specific interactions between T cells and 

antigen-presenting cells 13,14 (Fig. 1). 

RISING INCIDENCE OF ALLERGIC 

DISEASE 

The marked increase in the prevalence of atopic 

disease in western Europe, the United States, and 

Australasia during recent years indicates the importance 

of environmental influences. An informative 

example is the change in the incidence of seasonal 

allergic rhinitis and asthma after the reunification of 

Germany. These disorders were less common in East 

Germany than West Germany before reunification, 16 

whereas since reunification, the prevalence of atopy 

and hay fever, but not asthma, has increased among 

children who spent their early childhood in East Ger- 

30 · N Engl J Med, Vol. 344, No. 1 · January 4, 2001 · www.nejm.org 

Downloaded from www.nejm.org by VASSILAKOPOULOS THEODOROS MD on April 1, 2009 . 

Copyright © 2001 Massachusetts Medical Society. All rights reserved.

ADVANCES IN IMMUNOLOGY 

GATA-3 

c-maf 

PGE 2 

Nitric oxide 

Th2 

IFN-g 

High-affinity 

interactions 

between T cells and 

antigen-presenting cells 

 

Large amount 

of antigen 

 

Interleukin-4 Interleukin-10 and TGF-b Interleukin-12 

Interleukin-18 

Low-affinity 

interactions 

between T cells and 

antigen-presenting cells 

 

Small amount 

of antigen 

 

Th1 

CpG repeats from 

bacterial antigens 

Figure 1. Immunologic and Cellular Factors Regulating the Expression of Th1 and Th2 Cells. 

Whether the immune response is dominated by Th1 or Th2 cells is dependent on interleukin-12 and interleukin-4, respectively, as 

well as on the avidity of interactions between T cells and antigen-presenting cells and the amount of allergen to which the immune 

system is exposed (antigen). 13,14 In addition, the presence of cytidine–phosphate–guanosine (CpG) repeats derived from bacteria 

favors the Th1 phenotype, whereas the presence of transcription factors such as GATA-3 favors the Th2 phenotype, 15 as does the 

presence of c-maf and prostaglandin E 2 

(PGE 2 

). Nitric oxide favors the expression of Th2 cells by being less inhibitory to Th2 cells 

than Th1 cells, whereas in humans interleukin-10 and transforming growth factor b (TGF-b) generally dampen the responses of both 

types of cells. Interferon-g (IFN-g) inhibits Th2-mediated responses; both interleukin-12 and interleukin-18 release interferon-g from 

T cells. Interleukin-4 inhibits the expression of Th1 cells and promotes Th2-mediated responses. Green arrows indicate stimulatory 

effects, and red arrows inhibitory effects, of the cytokines. 

many. 17 This phenomenon raises the possibility that 

a Western lifestyle accounts for the increases in prevalence. 

Perhaps in Western countries the developing 

immune system is deprived of the microbial antigens 

that stimulate Th1 cells, because the environment is 

relatively clean and the use of antibiotics for minor 

illnesses in early life is widespread. 18 

The results of epidemiologic studies support this 

theory. Evidence that the bacteria that colonize the 

gastrointestinal tract prevent atopic sensitization was 

found in studies of one-year-old infants in countries 

with a low prevalence of atopy (Estonia) and a high 

prevalence (Sweden). Lactobacilli and eubacteria predominated 

in Estonian infants, whereas clostridia were 

more frequent in Swedish infants. 19 When studied one 

year later, the children with atopy were colonized 

less often by lactobacilli and had higher levels of aerobic 

bacteria (such as coliforms and Staphylococcus aureus) 

than children without atopy. 20 Moreover, atopy 

and allergic asthma were less frequent in populations 

exposed to Helicobacter pylori, Toxoplasma gondii, and 

hepatitis A virus. By producing an environment rich 

in interleukin-12, these microbes could drive a Th1- 

mediated response. This mechanism may explain why 

in Europe and Africa, farming or living in a rural 

community, which increases the likelihood of exposure 

to bacteria found in barns, protects against atopic 

disease. 21 

Other factors that may favor the Th2 phenotype 

in infants include diet and being born when pollen 

counts are high. 22 Furthermore, atopic allergic diseases 

are less common in younger children who have 

three or more older siblings and among children who 

have had measles or hepatitis A — another indication 

that repeated immune stimulation may protect against 

atopic allergy. 23 This view is supported by the study 

by Ball et al., who provided evidence that exposure 

of young children to older children at home or to 

other children at day-care centers protected against 

the development of asthma and frequent wheezing 

in childhood. 24 

This “hygiene” hypothesis is not easily reconciled 

N Engl J Med, Vol. 344, No. 1 · January 4, 2001 · www.nejm.org · 31 




with the increased prevalence among poor blacks in 

the United States of atopic asthma associated with 

sensitization to cockroaches and house-dust mites. 25,26 

However, we need more data on the rates of infection 

by foodborne and orofecal microbes in inner 

cities in the United States: the compounding effect 

of gut flora that does not protect against atopy and 

heavy exposure to allergens may explain this paradox. 

The development of specific allergic diseases may 

be related to alterations in the target organ. For example, 

the cofactors required for an asthma attack 

may include respiratory virus infections and exposure 

to allergens, tobacco smoke, and air pollutants. 27 These 

factors, alone or in combination, may alter immunoregulatory 

mechanisms at mucosal surfaces in ways 

that promote a Th2-mediated allergic inflammatory 

response (Fig. 2). 

ALLERGENS 

Many allergens are soluble proteins that function 

in their natural state as enzymes, by, for example, inducing 

proteolysis. Allergenic properties may be related 

to the enzymatic activity (e.g., increased mucosal 

permeability) and to aerodynamic properties, which 

in turn depend on the size of the particle. The major 

allergens of Western developed countries are Der p 1 

and Der p 2, from the house-dust mite (Dermatophagoides 

pteronyssinus); Fel d 1, from the cat (Felis domesticus); 

several tree allergens, including Bet v 1 from 

the birch tree (Betula verrucosa); and many grasses, 

such as Phl p 1 and Phl p 5 from timothy (Phleum 

pratense). The ragweed allergens Amb a 1, 2, 3, 5, 

and 6 from short ragweed (Ambrosia artemisiifolia) 

and Amb t 5 from giant ragweed (Ambrosia trifida) 

are important seasonal allergens in North America. 

Allergies to Hev b 1 through 7 from latex, the milky 

sap harvested from the rubber tree (Hevea brasiliensis), 

and Ara h 1, 2, and 3, which are highly allergenic peanut 

proteins, are increasingly important problems. 28 

GENETICS 

Atopic allergic diseases are familial and have a genetic 

basis. The difficulties of conducting genetic studies 

of allergy are due in part to the multiple markers 

for atopy and allergic diseases. For instance, atopy 

(manifested by positive skin-prick tests and elevated 

serum IgE levels) and asthma (manifested by airway 

hyperresponsiveness) are not always inherited togeth- 

Genetic Factors 

Presence of specific HLA alleles 

Polymorphisms of FceRI-b 

Polymorphisms of the interleukin-4 

family of cytokine genes 

Polymorphism of CD14 

Polymorphisms at other loci 

 

Environmental Factors 

Allergen sensitization 

Having few siblings 

Excessive hygiene 

Receipt of antibiotics in first 

2 years of life 

Vaccination and prevention of disease 

 

Atopy 

Defects in Target Organs 

Bronchial epithelium 

Skin 

Gut 

Triggers 

Viral infections 

Exposure to allergens 

Tobacco smoke 

Indoor and outdoor pollutants 

Th2-mediated allergic inflammation 

Figure 2. Factors Influencing the Development of Atopy and Allergic Inflammation Mediated by Th2 Cells (Atopic Allergic Disease). 

The induction of atopy is dependent on interactions between genes and the environment. The induction of atopic allergic disease 

may require further interactions between defects in the target organ and various environmental triggers. FceRI-b denotes the gene 

for the b chain of the high-affinity receptor for IgE. 





er. Techniques used to identify genes that are relevant 

to allergy and asthma include the candidate-gene approach, 

which depends on the identification of polymorphisms 

in a known gene, and positional cloning, 

which links the inheritance of a specific chromosomal 

region with the inheritance of a disease. 22 Such studies 

have linked several loci to atopy, but the clinical 

relevance of these findings is unclear. Examples are 

the associations between an allele of the HLA-DR 

locus and reactivity to the ragweed allergen Ra 5 29 

and the linkage of atopy to a polymorphism of the 

gene for the b chain of the high-affinity receptor for 

IgE (FceRI-b) 30 and to the interleukin-4 family of 

cytokine genes on chromosome 5. 31 By contrast, certain 

alleles of the tumor necrosis factor gene complex, 

although linked to asthma, are independent of 

serum IgE levels and other measures of atopy. 32 

Polymorphisms of the FceRI-b gene appear to be 

associated with equal frequency to severe atopy, asthma, 

and eczema. Also, positional cloning indicates 

that chromosomes 2q, 5q, 6q, 12q, and 13q contain 

loci linked to both asthma and atopy. 22 Polymorphisms 

in the gene encoding the high-affinity receptor 

for bacterial lipopolysaccharide (CD14) have been 

linked to total serum IgE levels and may help explain 

the association between childhood infections and the 

development of atopy. 33 

Several of the genes and genetic regions that have 

been linked to atopy and asthma have also been implicated 

in rheumatoid arthritis (chromosome 2) and inflammatory 

bowel disease (chromosomes 2 and 12). 22 

There has been recent interest in loci with pharmacologic 

relevance. Polymorphisms within the promoter 

region of the 5-lipoxygenase gene 34 and in the b-adrenergic 

receptor gene may regulate the response to inhibitors 

of 5-lipoxygenase or b-adrenergic agonists, 

respectively. 22,34 These findings raise the possibility that 

genotyping will become useful in planning therapy 

for asthma and other allergic diseases. 

IgE AND ITS RECEPTORS 

Acute allergic reactions result from the release of 

preformed granule-associated mediators, membranederived 

lipids, cytokines, and chemokines when an allergen 

interacts with IgE that is bound to mast cells 

or basophils by the a chain of the high-affinity IgE 

receptor (FceRI-a). 35 This receptor also occurs on 

antigen-presenting cells, where it can facilitate the 

IgE-dependent trapping and presentation of allergen 

to T cells. 36 Eosinophils also possess FceRI-a, but in 

these cells it is almost entirely intracellular; after being 

released by degranulation of the eosinophil, it may 

help regulate local levels of IgE. 37 

The most important inducers of the production of 

IgE are interleukin-4 and interleukin-13. These cytokines 

initiate transcription of the gene for the epsilon 

class of the constant region (C e 

) of the immunoglobulin 

heavy chain. The production of IgE also 

requires two transcription factors, nuclear factor kB 

and STAT-6; the former pathway involves the costimulatory 

molecules CD40 and the CD40 ligand 

(CD154), and the latter is activated when interleukin-4 

binds to the high-affinity a chain of the interleukin-4 

receptor. 38 

Allergens, including the products of some infectious 

microorganisms (e.g., Aspergillus fumigatus) and 

helminthic parasites, evoke Th2-mediated responses 

that are characterized by high serum levels of IgE, 

whereas other bacterial antigens (such as those associated 

with Listeria monocytogenes and Mycobacterium 

tuberculosis) elicit a Th1-mediated response that 

is dominated by cellular immunity (the appearance 

of cytotoxic T cells and delayed hypersensitivity). In 

this latter class of organisms, the DNA contains repeating 

sequences of cytosine and guanosine nucleosides 

called CpG repeats. These CpG repeats can 

bind to receptors on antigen-presenting cells and trigger 

the release of interleukin-12. This cytokine, which 

is produced almost exclusively by antigen-presenting 

cells, drives and maintains the Th1-mediated response. 

Furthermore, the interferon-g produced by activated 

Th1 cells 39 and interleukin-18, produced by macrophages, 

39 join forces to suppress the production of 

IgE antibodies. 40 Therefore, at least theoretically, interferon-g, 

interleukin-12, and interleukin-18, either 

alone or in combination, have therapeutic potential 

for inhibiting the synthesis of IgE. Furthermore (as 

discussed below), CpG repeats may redirect allergens 

to produce a Th1-mediated, rather than a Th2-mediated, 

immune response. 

The physiologic relevance of the low-affinity IgE 

receptor (CD23) remains speculative. It may be involved 

in antigen trapping and presentation, thereby 

augmenting the production of interleukin-4 or interleukin-13. 

41 It can, however, override the positive 

effects of antigen presentation by combining with excess 

IgE and antigen under conditions in which high 

levels of interleukin-4 have caused the up-regulation 

of this type of receptor. 42 

ALLERGIC INFLAMMATION 

In a person with atopy, exposure of the skin, nose, 

or airway to a single dose of allergen produces a cutaneous 

wheal-and-flare reaction, sneezing and runny 

nose, or wheezing within minutes. Depending on the 

amount of the allergen, these immediate hypersensitivity 

reactions are followed by a late-phase reaction, 

which reaches a peak six to nine hours after exposure 

to the allergen and then slowly resolves. In the skin, 

late-phase reactions are characterized by an edematous, 

red, and slightly indurated swelling; in the nose, 

by sustained blockage; and in the lung, by further 

wheezing. 

Immediate hypersensitivity is the basis of acute allergic 

reactions. It is caused by molecules released by 

mast cells when an allergen interacts with membrane- 





TABLE 1. THE ROLE OF CYTOKINES PRODUCED BY Th2 CELLS IN CHRONIC ALLERGIC INFLAMMATION. 

EVENT Th2-TYPE CYTOKINES INVOLVED OTHER FACTORS INVOLVED 

Production of IgE 

Development and accumulation of 

eosinophils and basophils 

Development of mast cells 

Interleukin-4, interleukin-9, and 

interleukin-13 

Interleukin-4, interleukin-5, interleukin-9, 

and interleukin-13 

Interleukin-4, interleukin-9, and interleukin-13 

Interferon-g, interleukin-12, and interleukin-18 

Interleukin-3, granulocyte–macrophage 

colony-stimulating factor, 

eotaxin-1, eotaxin-2, eotaxin-3, 

RANTES, monocyte chemotactic 

protein 3, monocyte chemotactic 

protein 4, and vascular-cell adhesion 

molecule 1 

Interleukin-3 and stem-cell factor 

Airway hyperresponsiveness Interleukin-9 and interleukin-13 Interleukin-11 and growth factors involved 

in remodeling 

Overproduction of mucus 

Interleukin-4, interleukin-9, and interleukin-13 

Histamine, leukotriene C 4 

, leukotriene 

D 4 

, substance P, and calcitonin-gene–related 

peptide 

bound IgE. The complex of allergen, IgE, and FceRI 

on the surface of the mast cell triggers a noncytotoxic, 

energy-dependent release of preformed, granuleassociated 

histamine and tryptase and the membranederived 

lipid mediators leukotrienes, prostaglandins, 

and platelet-activating factor. These mast-cell mediators 

have a critical role in anaphylaxis, rhinoconjunctivitis, 

and urticaria. The role of histamine in chronic 

asthma and eczema is probably minimal, however, as 

shown by the relative ineffectiveness of histamine antagonists 

in controlling these conditions. 

Mast cells produce the three cysteinyl leukotrienes 

C 4 

, D 4 

, and E 4 

, which cause the contraction of smooth 

muscles, vasodilatation, increased vascular permeability, 

and the hypersecretion of mucus when they bind 

to specific receptors. 43 

Eosinophils, macrophages, and monocytes are also 

major sources of cysteinyl leukotrienes. Mast cells also 

contain tryptase, a four-chain neutral protease that 

activates the protease-activated receptors on endothelial 

and epithelial cells. The activation of these receptors 

initiates a cascade of events, including the up-regulation 

of adhesion molecules that selectively attract 

eosinophils and basophils. 27 

In the cutaneous late-phase reaction, eosinophils 

and neutrophils accumulate, and then CD4+ T cells 

and basophils infiltrate the site. 44 Late-phase asthmatic 

45 and nasal 10 reactions have a similar pattern of 

cellular infiltration, although basophils are not prominent 

in the lower airways. 46 

Depending on the target organ, late-phase reactions 

can be provoked by the activation of mast cells or 

T cells. In the skin of atopic subjects and normal subjects, 

cross-linking of mast-cell–bound IgE with an 

antibody against IgE provokes both immediate hypersensitivity 

and late-phase reactions. 47 Late-phase reactions 

can be induced in patients with atopic asthma in 

the absence of immediate hypersensitivity involving 

mast cells. These reactions were induced in patients 

with asthma who were allergic to cats by an intradermal 

injection of peptides derived from a cat allergen. 48 

The fact that these late-phase reactions were independent 

of IgE and were major-histocompatibility-complex 

(MHC)–restricted indicates that the activation 

of T cells alone is sufficient to initiate airway narrowing 

in patients with allergic asthma. 

Antigen-presenting cells are critical in initiating 

and controlling allergic inflammation. Dendritic cells 

and cutaneous Langerhans’ cells are particularly important 

in asthma and atopic eczema, respectively. 

They present antigen to CD4+ Th2 cells in an MHC 

class II–restricted fashion. Overproduction of the 

granulocyte–macrophage colony-stimulating factor in 

the airway mucosa of patients with asthma enhances 

antigen presentation and increases the local accumulation 

of macrophages. 12 Alveolar macrophages obtained 

from patients with asthma by bronchoalveolar 

lavage present allergen to CD4+ T cells and stimulate 

the production of Th2-type cytokines, 49 whereas alveolar 

macrophages from control subjects do not. 

Th2-type cytokines such as interleukin-4, 5, 9, 

and 13 influence a wide range of events associated 

with chronic allergic inflammation. Interleukin-4 and 

interleukin-13 stimulate the production of IgE and 

vascular-cell adhesion molecule 1; interleukin-5 and interleukin-9 

are involved in the development of eosinophils; 

interleukin-4 and interleukin-9 promote 

the development of mast cells; interleukin-9 and interleukin-13 

help promote airway hyperresponsiveness 50 ; 

and interleukin-4, interleukin-9, and interleukin-13 





Membrane-bound IgE 

Histamine, leukotrienes, 

platelet-activating factor 

Mast cell 

Interleukin-4 

Interleukin-5 

Acute Allergic 

Reaction 

Wheezing 

Urticaria 

Sneezing, rhinorrhea, 

conjunctivitis 

B cell 

Allergen 

IgE production 

Eosinophil 

Basic proteins, 

leukotrienes, 

platelet-activating 

factor 

Interleukin-4 

Dendritic 

 

cell 

Th2 

Interleukin-5 

Chronic Allergic 

Reaction 

MHC class II 

molecule 

T-cell receptor 

Histamine-releasing 

factor, neuropeptides 

Neurotrophins 

Mast cell 

Histamine, 

lipids, 

cytokines 

Further wheezing 

Sustained blockage 

of the nose 

Eczema 

 

Neuropeptides 

Figure 3. Pathways Leading to Acute and Chronic Allergic Reactions. 

Acute allergic reactions are due to the antigen-induced release of histamine and lipid mediators from mast cells. In the skin and 

upper airways, basophils (not shown) may also participate in allergic tissue reactions. Chronic allergic reactions, including the latephase 

reaction, may depend on a combination of pathways, including the recruitment of eosinophils, the liberation of mast-cell 

products by histamine-releasing factors, 62 and neurogenic inflammation involving neurotrophins and neuropeptides. MHC denotes 

major histocompatibility complex. 

promote the overproduction of mucus (Table 1). Eosinophils 

can injure mucosal surfaces by releasing toxic 

basic proteins, cysteinyl leukotrienes, and plateletactivating 

factor. They also damage inhibitory M2 

muscarinic receptors, which may allow unchecked cholinergic 

responses in patients with asthma. 51 By contrast, 

eosinophils may also repair damage, since they 

produce fibrogenic growth factors and matrix metalloproteinase, 

which remodel airway tissue in asthma. 52 

Interleukin-5 releases both mature and immature 

eosinophils from the bone marrow, 53 regulates the expression 

of the transmembrane isoform of its own receptor, 

54 and is essential for the terminal differentiation 

of committed eosinophil precursors. 55 The preferential 

accumulation of eosinophils occurs through the interactions 

between selective adhesion molecules (a 4 

b 1 

integrin and vascular-cell adhesion molecule), the migration 

of eosinophils toward receptors for CC chemokines 

as a result of recruitment by eotaxin-1, eotaxin-2, 

eotaxin-3, RANTES, monocyte chemotactic 

protein (MCP) 3 and MCP-4; prolonged survival (delayed 

apoptosis) under the influence of interleukin-5, 

interleukin-3, and granulocyte–macrophage colonystimulating 

factor; and the local differentiation of tis- 





sue-infiltrating eosinophil precursors induced by interleukin-5. 

56 

Allergic inflammation may also follow the release 

of neuropeptides from nerve cells by the action of 

nerve growth factor, brain-derived neurotrophic factor, 

and neurotrophin-3. 57,58 These neurotrophins are secreted 

by macrophages, T cells, eosinophils, and mast 

cells. 58 Neuropeptides, particularly substance P, calcitonin-gene–related 

peptide, and neurokinin A (all 

of which are located predominantly in sensory neurons, 

but also in inflammatory cells), cause characteristic 

features of allergic inflammation, including vasodilatation, 

increased vascular permeability, and in the 

lung, contraction of the smooth muscles of the airway 

and hypersecretion of mucus. 59 They also release 

histamine from mast cells in the lungs. 60 Tryptase can 

also trigger nerve cells to release neuropeptides by 

binding to protease-activated receptors. Further amplifications 

of chronic allergic reactions may be mediated 

by histamine-releasing factor or factors. 61 Pathways 

leading to acute and chronic allergic reactions 

are shown in Figure 3. 

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